功能丧失的线粒体DNA聚合酶玛变体导致血管光滑肌细胞分泌一种扩散性线粒体发生因子
Samantha Rothwell1, Irvin Ng1, Sophia Shalchy-Tabrizi1
1Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
Frontiers in physiology
|March 4, 2025
概括
与高血压相关的线粒体DNA聚合酶 (POLG) 变体会损害线粒体的健康,导致细胞释放促进生长的信号. 这种信号可能驱动血管重塑,并导致耐药高血压.
科学领域:
- 心血管生物学 心血管生物学
- 线粒体生物学 线粒体生物学
- 遗传学 遗传学 是一个
背景情况:
- 线粒体功能障碍有助于血管衰老和疾病.
- 线粒体DNA (mtDNA) 聚合酶 (POLG) 对mtDNA复制和线粒体健康至关重要.
- 功能丧失的POLG变体与高血压有关.
研究的目的:
- 为了研究高血压患者中发现的POLG变体对血管光滑肌细胞的影响.
- 确定受损的POLG功能是否促进光滑肌肉细胞增大/增多,从而导致与高血压相关的血管改造.
主要方法:
- 在A7r5细胞中过度表达了POLG变体 (p.Tyr955Cys,p.Arg964Cys,p.Asn1098Ile,p.Arg1138Cys).
- 用于结构预测的AlphaFold建模.
- 评估mtDNA拷贝数,线粒体膜潜力,基因氧物种和氧气消耗.
- 细胞增殖测定和条件介质分析.
- 药理抑制研究.药理抑制研究.
主要成果:
- 波尔格变异减少了mtDNA拷贝数,p.Tyr955Cys显示了最大的减少.
- 在A7r5和HeLa细胞中,某些POLG变体 (例如,p.Tyr955Cys) 增加了细胞密度和生长.
- 从变体转移的细胞中获得的条件介质在原始培养物中刺激了增殖.
- 韦德洛拉克顿和米托特姆波尔抑制了特定的POLG变体的线粒生成效应.
结论:
- 波尔格功能障碍会触发分泌一种线粒基信号,独立于显著的mtDNA复制数减少.
- 这种分泌的信号可能会诱导缩性重塑,可能会导致POLG变体患者的耐药高血压.
相关概念视频
Regulation of Angiogenesis and Blood Supply
2.5K
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
2.5K
Abnormal Proliferation
4.4K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.4K
TGF - β Signaling Pathway
7.2K
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
7.2K
Animal Mitochondrial Genetics
7.4K
Among all the organelles in an animal cell, only mitochondria have their own independent genomes. Animal mitochondrial DNA is a double-stranded, closed-circular molecule with around 20,000 base pairs. Mitochondrial DNA is unique in that one of its two strands, the heavy, or H, -strand is guanine rich, whereas the complementary strand is cytosine rich and called the light, or L, -strand. Compared to nuclear DNA, mitochondrial DNA has a very low percentage of non-coding regions and is marked by...
7.4K
Mitogens and the Cell Cycle
6.4K
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.4K
Small GTPases - Ras and Rho
3.9K
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
3.9K


